Chimeric coronavirus spike combining SARS-CoV-2 RBD and scaffold domains from HKU-1 elicits potent T helper cell and neutralising antibody responses in murine and non-human primate models 4642

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Abstract Description The receptor binding domain (RBD) of the SARS-CoV-2 spike is the major target for neutralising antibodies elicited by current vaccines. However, RBD subunit vaccines are poorly immunogenic, due to insufficient CD4 T follicular helper (TFH) cell epitopes, consequently driving poor germinal centre (GC) responses. We engineered a novel chimeric trimer-RBD (CTR) glycoprotein, replacing the RBD of human coronavirus HKU-1 spike with SARS-CoV-2 RBD (Wuhan-Hu-1 or BA.2). This strategy leverages HKU-1 scaffold CD4 epitopes while preserving SARS-CoV-2 RBD neutralising targets, with antigenicity confirmed by monoclonal antibodies. In C57BL/6 mice, CTR-BA.2 prime-boost vaccination elicited high anti-BA.2-RBD IgG titres (∼104) and BA.2 neutralisation (IC50: 4.0x102), matching native spike responses. GC B cells elicited by CTR-BA.2 were predominantly Wuhan-Hu-1+/BA.2+ cross-reactive, while 25.3% of TFH cells, measured by CD154+, recognised HKU-1 epitopes, demonstrating scaffold-directed T cell help. Macaques prime-boost immunised with CTR-Wuhan-Hu-1 elicited high anti-RBD IgG (∼104) and neutralising responses (IC50: 7.5x102), comparable to native spike (n = 5/group). RBD-specific GC B cells (BCL-6+CD95+) were present at elevated levels in draining lymph nodes of native (1.94%) or CTR spike-vaccinated (1.62%) animals vs non-draining sites. Our findings establish the chimeric glycoprotein design as a strategy to overcome the poor immunogenicity of the SARS-CoV-2 RBD by engaging CD4 TFH cells. Funding Sources Supported by the National Health and Medical Research Council (Australia) (2009711, 2026762, 2009308) and Medical Research Future Fund (Australia) (2013870). Topic Categories Vaccines and Immunotherapy (VAC)

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